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Norepinephrine Transporter Function and Autonomic Control of Metabolism

German Institute of Human Nutrition (M.B., S.K.), 14558 Potsdam, Germany; Franz-Volhard Clinical Research Center (C.S., J.T., G.K., A.M.S., F.C.L., J.J.), Medical Faculty of the Charité, Humboldt-University, Berlin 13125, Germany; Department of Internal Medicine and Endocrinology (N.J.C.), Herlev Hospital, University of Copenhagen, 2730 Copenhagen, Denmark; and Autonomic Dysfunction Service (I.B.), Vanderbilt University, Nashville, Tennessee 37232

Address all correspondence and requests for reprints to: Jens Jordan, M.D., Clinical Research Center, Haus 129, Franz-Volhard-Clinic, Humboldt University, Wiltbergstrasse 50, 13125 Berlin, Germany. E-mail: jordan{at}fvk-berlin.de.

Abstract

Genetic variability, numerous medications, and some illicit drugs influence norepinephrine transporter (NET) function; however, the metabolic consequences of NET inhibition are poorly understood. We performed a randomized, double-blind, cross-over trial in 15 healthy subjects who ingested 8 mg of the selective NET inhibitor reboxetine or placebo. Energy expenditure and substrate oxidation rates were determined by indirect calorimetry before and during iv infusion of 0.25, 0.5, 1, and 2 µg isoproterenol/min. Adipose tissue metabolism was studied by microdialysis before and during local isoproterenol perfusion. At rest, energy expenditure and substrate oxidation rates did not differ between reboxetine and placebo treatment. At 1 µg/min isoproterenol, energy expenditure was significantly increased in men (+15%) and women (+20%) with both reboxetine and placebo treatment. However, carbohydrate oxidation rate was significantly higher with reboxetine compared with placebo. Baseline and isoproterenol-stimulated adipose tissue blood flow was about 2-fold higher with reboxetine vs. placebo. Furthermore, glucose supply and metabolism was significantly increased and lipid mobilization much more stimulated in adipose tissue under reboxetine when compared with placebo at all isoproterenol concentrations used. We conclude that acute NET inhibition increases adipose tissue glucose uptake and metabolism. While lipid mobilization is increased, overall lipid oxidation is decreased during ß-adrenergic stimulation. This effect cannot be explained by increased systemic or adipose tissue norepinephrine concentrations. Instead, NET inhibition may sensitize adipose tissue to ß-adrenergic stimulation.

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